Mechanism-related patterns of in vitro sensitivity have been recognized since very early in the development phase of the current NCI primary antitumor drug screen. Development of the "Compare" programs has allowed routine comparison of patterns produced by unknown compounds with the standard agent database (which contains prototype agents representing all known mechanistic classes). In several instances this has allowed insight into the potential mechanism of action of the unknown compound. In this project we have begun to dissect the molecular basis for the mechanism-related patterns. Because the multidrug-resistant (MDR) phenotype affects several mechanistic classes, we initiated work in this area. Several MDR cell lines were identified in the screening panels. Analysis of O6-methylguanine-DNA methyltransferase (MGMT) mRNA levels has revealed the presence of several cell lines which are hypersensitive to alkylating agents, presumably on the basis of deficient DNA repair. Through evaluation of additional genes we hope to gain a more complete understanding of the drug sensitivity patterns observed in the screening data.